長QT綜合征抗心律失常藥物PPT課件

1、第1頁/共42頁第2頁/共42頁第3頁/共42頁第4頁/共42頁GENETIC FACTORCONGENITAL ACQUIREDLONG QT SYNDROMELONG QT SYNDROME( FORME FRUSTE ) - IT SHOULD BE REMEMBERED THE LOW PENETRANCE OF GENETIC DISORDERS - BETWEEN ENVIRONMENTAL FACTORS THE MOST IMPORTANT SEEMS TO BE THE CONCOMITANT HYPOKALEMIAFIGURE 1 - SCHEMATIC REPRESENT

2、ATION OF DIFFERENT FACTORS BEING INVOLVED IN TDP INDUCTIONTRIGGER (DRUGS)ENVIRONMENTAL FACTORS第5頁/共42頁Genetic characterization of congenital LQT syndrome第6頁/共42頁Mechanims of Drug-induced QT Prolongation and TdP 1lThe blockade of Ikr current by antiarrhythmic drugs that are capable of prolonging the

3、action potential duration is at least in part responsible for their proarrhythmic effect. lIt is interesting to note that many other drugs that cause the development of early afterdepolarizations and TdP block the Ikr channel. lThe incidence of TdP remain low, however, and not all drugs that block I

4、kr have the same arrhythmogenic potential. The precise reason for the different effects of Ikr blocker is unknown.第7頁/共42頁Mechanims of Drug-induced QT Prolongation and TdP 2lThus, in an ordinary situation, the administration of an Ikr blocker might not prolong the QT interval.lHowever in the presenc

5、e of an otherwise subclinical lesion in the repolarization mechanisms (i.e. reduced repolarization reserve), the same Ikr blocker may precipitate marked QT prolongation and TdP.第8頁/共42頁Mechanims of Drug-induced QT Prolongation and TdP 3lThe causes for these lesions may be acquired (e.g. myocardial i

6、nfarction, congestive heart failre, ischemia, etc.) or congenital (formes frustes of congenital long QT syndrome).lThe extent of QT prolongation and risk of TdP associated with a given drug may not be linearly related to the dose of plasma level of the drug, because patient and metabolic factors are

7、 also important (e.g. gender, electrolyte levels, etc)lThere is not a simple relationship of drug-induced QT prolongation and the likelihood of the development of TdP which can sometimes occur without any noticeable prolongation of the QT interval.第9頁/共42頁Torsades de Pointes第10頁/共42頁Factors Modulate

8、 the Effects of Drugs That Block IKr Hypokalemia and hypomagnesemia Hypertrophy and heart failure Gender Metabolic factors Sympathetic activity Multiple actions of drugs that block IKr “Forme fruste” of the congenital long QT syndrome 第11頁/共42頁Part 1: Cardiac Drugs able to induce QT Prolongation and

9、 TdP第12頁/共42頁Class Antiarrhythmics Quinidinel Blocks the delayed rectifier Ikr as well as IKsl Quinidine Syncopel Causes QT prolongation early during therapy , usually within 1 weekl QT prolongation 1.5%l TdP 1% 8.8%, especially when QT interval 520ms, hypokalemia and bradycardia 第13頁/共42頁第14頁/共42頁C

10、lass III Antiarrhythmic Drugs 1d, l Sotalol Blocks the delayed rectifier Ikr potassium current No effect on the slow component Iks current Additional -blocking effect Incidence of TdP increases with dose and the baseline values of the QT interval. TdP occurred early even with low doses of oral d,l-s

11、otalol, especially in patients with congestive heart failure and low ejection fraction. 第15頁/共42頁第16頁/共42頁Drug induced TDP: comparison between Quinidine and Sotalol第17頁/共42頁Class III Antiarrhythmic Drugs 2 AmiodaronelUnique drug which possesses pharmacological properties from all four antiarrhythmic

12、 classeslHas the same potent effects on QT prolongation as other Class III agents, but the associated incidence of TdP is very low.lTdP usually occurs during concomitant therapy with other QT prolonging drugs or in the context of severe electrolyte disturbance.lIntravenous amiodarone is also safe an

13、d effective for the treatment of ventricular tachyarrhythmias.第18頁/共42頁第19頁/共42頁 d- Sotalol Ibutilide Azimilide Tedisamil Ersentilide Dofetilide Dronedarone AlmokalantNew Class III drugs第20頁/共42頁第21頁/共42頁第22頁/共42頁第23頁/共42頁第24頁/共42頁第25頁/共42頁Part 2: Acquired Long QT Syndrome by Non- Antiarrhythmic Dru

14、gs第26頁/共42頁第27頁/共42頁Part 3 Drug Drug Interaction第28頁/共42頁Cytochrome P450(CYP) enzymes are divided into two classes on the basis of the fundamental characteristics of their substratesl Those primarily involved in the metabolism of drugs and other xenobioticsl Those involved in the biosynthesis and me

15、tabolism of steroid hormones and other endobiotics第29頁/共42頁第30頁/共42頁Part 4 How to Avoid Drug-Induced Torsades de Pointes第31頁/共42頁第32頁/共42頁第33頁/共42頁第34頁/共42頁第35頁/共42頁Flow chart for Sotalol administration 第36頁/共42頁Conclusions 1lThe discordance between QT prolongation and the incidence of TDP among ant

16、iarrhythmic drugs that prolong ventricular refractoriness has stimulated immense interest in separating the salutary terapeutic effects from the adverse proarrhythmic action of antiarrhytmic drugs.lRapidly expanding knowledge of ion channel kinetics and structure, will aid the development of new dru

17、gs with specific profiles of channel blocking properties which have an effective antiarrhythmic action with minimal proarrhythmic potential.第37頁/共42頁Conclusions 2lFor non antiarrhythmic drugs wich prolongs QT interval, dose, duration of treatment, route of administration and magnitude of liver and k

18、idney clearances will affect the intensity and duration of the exposure to the drug. lThe most suitable raccomandation for a prescribing physician for both antiarrhythmic and non cardiac drugs is to consult the drug information sheets, the reference books, national formularies, and other drug compendia, to avoid unwanted drug interactions and additive effects on Ikr channels.第38頁/共42頁Conclusions 3lThe overall incidence of TdP in patients who use drugs that block Ikr is low (3%), and not all drugs that block Ikr have the same arrhythmogenic pot